2. Academic Validation
  3. Structure-Guided Discovery of cis-Hexahydro-pyrido-oxazinones as Reversible, Drug-like Monoacylglycerol Lipase Inhibitors

Structure-Guided Discovery of cis-Hexahydro-pyrido-oxazinones as Reversible, Drug-like Monoacylglycerol Lipase Inhibitors

  • J Med Chem. 2024 Oct 24;67(20):18448-18464. doi: 10.1021/acs.jmedchem.4c01769.
Bernd Kuhn 1,  Martin Ritter 1,  Benoit Hornsperger 1,  Charles Bell 1,  Buelent Kocer 1,  Didier Rombach 1,  Marius D R Lutz 1,  Luca Gobbi 1,  Martin Kuratli 1,  Christian Bartelmus 1,  Markus Bürkler 1,  Raffael Koller 1,  Paolo Tosatti 1,  Iris Ruf 1,  Melanie Guerard 1,  Anto Pavlovic 1,  Juliane Stephanus 1,  Fionn O'Hara 1,  Dennis Wetzl 1,  Wiebke Saal 1,  Martine Stihle 1,  Doris Roth 1,  Melanie Hug 1,  Sylwia Huber 1,  Dominik Heer 1,  Carsten Kroll 1,  Andreas Topp 1,  Manfred Schneider 1,  Jürg Gertsch 2,  Sandra Glasmacher 2,  Mario van der Stelt 3,  Andrea Martella 3,  Matthias Beat Wittwer 1,  Ludovic Collin 1,  Jörg Benz 1,  Hans Richter 1,  Uwe Grether 1
Affiliations

Affiliations

  • 1 Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, Basel 4070, Switzerland.
  • 2 Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bern 3012, Switzerland.
  • 3 Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Leiden 2300 CC, Netherlands.
PMID: 39360636 DOI: 10.1021/acs.jmedchem.4c01769
Abstract

Monoacylglycerol Lipase (MAGL) is a key enzyme involved in the metabolism of the endogenous signaling ligand 2-arachidonoylglycerol, a neuroprotective endocannabinoid intimately linked to central nervous system (CNS) disorders associated with neuroinflammation. In the quest for novel MAGL inhibitors, a focused screening approach on a Roche library subset provided a reversible benzoxazinone hit exhibiting high ligand efficiency. The subsequent design of the three-dimensional cis-hexahydro-pyrido-oxazinone (cis-HHPO) moiety as benzoxazinone replacement enabled the combination of high MAGL potency with favorable ADME properties. Through enzymatic resolution an efficient synthetic route of the privileged cis-(4R,8S) HHPO headgroup was established, providing access to the highly potent and selective MAGL Inhibitor 7o. Candidate molecule 7o matches the target compound profile of CNS drugs as it achieves high CSF exposures after systemic administration in rodents. It engages with the target in the brain and modulates neuroinflammatory processes, thus holding great promise for the treatment of CNS disorders.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168145
    MAGL Inhibitor